Nitrostat®

 

(nitroglycerin) Tablets, USP

DRUG DESCRIPTION

What are the possible side effects of nitroglycerin (Nitrolingual, Nitrolingual Duo Pack, Nitroquick, Nitrostat)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

fast, slow, pounding, or uneven heart rate;

blurred vision or dry mouth;

nausea, vomiting, sweating, pale skin, feeling like you might pass out; or

fever, sore throat, and…

Read All Potential Side Effects and See Pictures of Nitrostat »

Nitrostat is a stabilized sublingual compressed nitroglycerin tablet that contains 0.3 mg (1/200 grain), 0.4 mg (1/150 grain), or 0.6 mg (1/100 grain) nitroglycerin; as well as lactose monohydrate, NF; glyceryl monostearate, NF; pregelatinized starch, NF; calcium stearate, NF powder; and silicon dioxide, colloidal, NF.

Nitroglycerin, an organic nitrate, is a vasodilating agent. The chemical name for nitroglycerin is 1, 2, 3 propanetriol trinitrate and the chemical structure is:

Molecular weight: 227.09

Last reviewed on RxList: 8/24/2009

Nitrostat Indications & Dosage

 

INDICATIONS

Nitroglycerin is indicated for the acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease.

DOSAGE AND ADMINISTRATION

One tablet should be dissolved under the tongue or in the buccal pouch at the first sign of an acute anginal attack. The dose may be repeated approximately every 5minutes, until relief is obtained. If the pain persists after a total of3 tablets in a15-minute period, prompt medical attention is recommended. Nitrostat may be used prophylactically5 to 10 minutes prior to engaging in activities which might precipitate an acute attack.

During administration the patient should rest, preferably in the sitting position. No dosage adjustmentis required in patients with renal failure.

HOW SUPPLIED

Nitrostat is supplied as white, round, flat-faced tablets in 3 strengths (0.3 mg, 0.4 mg, and 0.6 mg) in bottles containing 100 tablets each, with color-coded labels, and in color-coded Patient Convenience Packages of 4 bottles of 25 tablets each.

0.3 mg (½00 grain): Coded “N” on one side and “3” on the other
N 0071 -0417-24—Bottle of 100 tablets

0.4 mg (1/150 grain): Coded “N” on one side and “4” on the other
N 0071-0418-13—Convenience Package
N 0071-0418-24—Bottle of100 tablets

0.6 mg (1/100 grain): Coded “N” on one side and “6” on the other.
N 0071-0419-24—Bottle of100 tablets

Store at Controlled Room Temperature 20°-25°C (68°-77°F) [see USP].

Distributed by: Parke-Davis., Division of Pfizer Inc, NY, NY 10017. December 2005

Last reviewed on RxList: 8/24/2009

Nitrostat Side Effects & Drug Interactions

 

SIDE EFFECTS

Headache which may be severe and persistent may occur immediately after use. Vertigo, dizziness, weakness, palpitation, and other manifestations of postural hypotension may develop occasionally, particularly in erect, immobile patients. Marked sensitivity to the hypotensive effects of nitrates (manifested by nausea, vomiting, weakness, diaphoresis, pallor, and collapse) may occur at therapeutic doses. Syncope due to nitrate vasodilatation has been reported. Flushing, drug rash, and exfoliative dermatitis have been reported in patients receiving nitrate therapy.

DRUG INTERACTIONS

Patients receiving antihypertensive drugs, beta-adrenergic blockers, or phenothiazines and nitrates should be observed for possible additive hypotensive effects. Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly. Concomitant use of nitrates and alcohol may cause hypotension.

The vasodilatory and hemodynamic effects of nitroglycerin maybe enhanced by concomitant administration of aspirin. Intravenous administration of nitroglycerin decreases the thrombolytic effect of alteplase. Therefore, caution should be observed in patients receiving sublingual nitroglycerin during alteplase therapy.

Intravenous nitroglycerin reduces the anticoagulant effect of heparin and activated partial thromboplastin times (APTT) should be monitored in patients receiving heparin and intravenous nitroglycerin. It is not known if this effect occurs following single sublingual nitroglycerin doses.

Tricyclic antidepressants (amitriptyline, desipramine, doxepin, others) and anticholinergic drugs may cause dry mouth and diminished salivary secretions. This may make dissolution of sublingual nitroglycerin difficult. Increasing salivation with chewing gum or artificial saliva products may prove useful in aiding dissolution of sublingual nitroglycerin.

Oral administration of nitroglycerin markedly decreases the first-pass metabolism of dihydroergotamine and subsequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris. Therefore, patients receiving sublingual nitroglycerin should avoid ergotamine and related drugs or be monitored for symptoms of ergotism if this is not possible. Administration of nitroglycerin is contraindicated in patients who are using Viagra (sildenafil citrate). Viagra has been shown to potentiate the hypotensive effects of organic nitrates.

A decrease in therapeutic effect of sublingual nitroglycerin may result from use of long-acting nitrates.

Drug/Laboratory Test Interactions

Nitrates may interfere with the Zlatkis-Zak color reaction causing a false report of decreased serum cholesterol.

Last reviewed on RxList: 8/24/2009

Nitrostat Warnings & Precautions

 

WARNINGS

The benefits of sublingual nitroglycerin in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use nitroglycerin in these conditions, careful clinical or hemodynamic monitoring must be used because of the possibility of hypotension and tachycardia.

PRECAUTIONS

General

Only the smallest dose required for effective relief of the acute anginal attack should be used. Excessive use may lead to the development of tolerance. Nitrostat tablets are intended for sublingual or buccal administration and should not be swallowed. Severe hypotension, particularly with up right posture, may occur with small doses of nitroglycerin. This drug should therefore be used with caution in patients who may be volume-depleted or who, for whatever reason, are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

As tolerance to other forms of nitroglycerin develops, the effects of sublingual nitroglycerin on exercise tolerance, although still observable, is blunted.

In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance rarely occurs. Chest pain, acute myocardial infraction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence.

Several clinical trials of nitroglycerin patches or infusions in patients with angina pectoris have evaluated regimens which incorporated a 10 to 12 hour nitrate free interval. In some of these trials, an increase in the frequency of anginal attacks during the nitrate free interval was observed in a small number of patients. In one trial, patients had decreased exercise tolerance at the end of the nitrate interval. Hemodynamic rebound has been observed only rarely; on the other hand, few studies were so designed that rebound, if it had occurred, would have been detected.

Nitrate tolerance as a result of sublingual nitroglycerin administration is probably possible, but only in patients who maintain high continuous nitrate levels for more than 10 or12 hours daily. Such use of sublingual nitroglycerin would entail administration of scores of tablets daily and is not recommended.

The drug should be discontinued if blurring of vision or drying of the mouth occurs. Excessive dosage of nitroglycerin may produce severe headaches.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal carcinogenesis studies with sublingually administered nitroglycerin have not been performed.

Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years developed dose-related fibrotic and neoplastic changes in liver, including carcinomas and interstitial cell tumors in testes. At high dose the incidences of hepatocellular carcinomas in males was 48% and in females was 33% compared to 0% in untreated controls. Incidences of testicular tumors were 52% vs 8% in controls. Lifetime dietary administration of up to 1058 mg/kg/day of nitroglycerin was not tumorigenic in mice.

Nitroglycerin was weakly mutagenic in Ames tests performed in 2 different laboratories. Nevertheless, there was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with doses up to about 363 mg/kg/day, PO, or in ex vivo cytogenetic tests in rat and dog tissues.

In a 3-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for 6 months prior to mating of the F0 generation with treatment continuing through successive F1 and F2 generations. The high dose was associated with decreased feed intake and body weight gain in both sexes at all matings. No specific effect on the fertility of the F0 generation was seen. Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and aspermatogenesis in the high-dose males. In this 3-generation study there was no clear evidence of teratogenicity.

Pregnancy Category C

Animal reproduction and teratogenicity studies have not been conducted with nitroglycerin sublingual tablets. Teratology studies in rats and rabbits, however, were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested. There are no adequate and well-controlled studies in pregnant women. Nitroglycerin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitroglycerin is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of nitroglycerin in pediatric patients have not been established.

Geriatric Use

Clinical studies of Nitrostat did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Last reviewed on RxList: 8/24/2009

Nitrostat Overdosage & Contraindications

 

OVERDOSE

Hemodynamic Effects

The effects of nitroglycerin overdose are generally the results of nitroglycerin’s capacity to induce vasodi-latation, venous pooling, reduced cardiac output, and hypotension. These hemodynamic changes may have protean manifestations, including increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; tachycardia; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); dyspnea, later followed by reduced ventilatory effort, diaphoresis, with the skin either flushed or cold and clammy; heartblock and bradycardia; paralysis; coma; seizures; and death.

No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of veno dilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient’s legs maybe sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary. The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good. In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of nitroglycerin overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia

Methemoglobinemia has been rarely reported in association with organic nitrates. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial PO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, may be required.

CONTRAINDICATIONS

Allergic reactions to organic nitrates are extremely rare, but they do occur. Nitroglycerin is contraindicated in patients who are allergic to it.

Sublingual nitroglycerin therapy is contraindicated in patients with early myocardial infarction, severe anemia, increased intracranial pressure, and those with a known hypersensitivity to nitroglycerin.

Administration of Nitrostat (nitroglycerin tablets, USP) is contraindicated in patients who are using Viagra® since Viagra has been shown to potentiate the hypotensive effects of organic nitrates.

Last reviewed on RxList: 8/24/2009

Nitrostat Clinical Pharmacology

 

CLINICAL PHARMACOLOGY

The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle. Although venous effects predominate, nitroglycerin produces, in a dose-related manner, dilation of both arterial and venous beds. Dilation of postcapillary vessels, including large veins, promotes peripheral pooling of blood, decreases venous return to the heart, and reduces left ventricular end-diastolic pressure (preload). Nitroglycerin also produces arteriolar relaxation, thereby reducing peripheral vascular resistance and arterial pressure (afterload), and dilates large epicardial coronary arteries; however, the extent to which this latter effect contributes to the reliefofexertional angina is unclear.

Therapeutic doses of nitroglycerin may reduce systolic, diastolic, and mean arterial blood pressure. Effective coronary perfusion pressure is usuallymaintained, butcan be compromised ifblood pressure falls excessivelyor increased heartrate decreases diastolic filling time.

Elevated central venous and pulmonary capillarywedge pressures, and pulmonary and systemic vascularresistance are also reduced by nitroglycerin therapy. Heart rate is usually slightly increased, presumably due to a compensatory response to the fall in blood pressure. Cardiac index may be increased, decreased, or unchanged. Myocardial oxygen consumption or demand (as measured by the pressure-rate product, tension-time index, and stroke-work index) is decreased and a more favorable supply-demand ratio can be achieved. Patients with elevated left ventricular filling pressures and increased systemic vascular resistance in association with a depressed cardiac index are likely to experience an improvement in cardiac index. In contrast, when filling pressures and cardiac index are normal, cardiac indexmaybe slightlyreduced following nitroglycerin administration.

Mechanism of Action

Nitroglycerin forms free radical nitric oxide (NO) which activates guanylate cyclase, resulting in an increase of guanosine 3’5′ monophosphate (cyclic GMP) in smooth muscle and othertissues. These events lead to dephosphorylation of myosin lightchains, which regulate the contractile state in smooth muscle, and resultin vasodilatation.

Pharmacodynamics

Consistent with the symptomatic relief of angina, digital plethysmography indicates that onset of the vasodilatory effect occurs approximately 1 to 3 minutes after sublingual nitroglycerin administration and reaches a maximum by 5 minutes postdose. Effects persistfor atleast25 minutes following Nitrostatadministration.

Pharmacokinetics and Drug Metabolism

Absorption

Nitroglycerin is rapidly absorbed following sublingual administration of Nitrostat tablets. Mean peak nitroglycerin plasma concentrations occur at a mean time of approximately 6 to 7 minutes postdose (Table 1). Maximum plasma nitroglycerin concentrations (Cmax) and area underthe plasma concentration-time curves (AUC) increase dose-proportionallyfollowing 0.3 to 0.6 mg Nitrostat. The absolute bioavailabilityofnitroglycerin from Nitrostattabletsis approximately 40% but tends to be variable due to factors influencing drug absorption such as sublingual hydration and mucosal metabolism.

Table 1

	Mean Nitroglycerin (SD) Values
	2 x 0.3 mg	1 x 0.6 mg
Parameter	Nitrostat Tablets	Nitrostat Tablets
Cmax, ng/mL	2.3(1.7)	2.1 (1.5)
tmax, min	6.4(2.5)	7.2 (3.2)
AUC(0-∞), min	14.9 (8.2)	14.9(11.4)
t½, min	2.8(1.1)	2.6 (0.6)

Distribution

The volume of distribution (Vato) of nitroglycerin following intravenous administration is 3.3 L/kg. At plasma concentrations between 50 and 500 ng/mL, the binding of nitroglycerin to plasma proteins is approximately 60%, while that of 1.2- and 1,3-dinitroglycerin is 60% and 30%, respectively.

Metabolism

A liver reductase enzyme is of primary importance in the metabolism of nitroglycerin to glycerol di- and mononitrate metabolites and ultimately to glycerol and organic nitrate. Known sites of extrahepatic metabolism include red blood cells and vascular walls. In addition to nitroglycerin, 2 major metabolites 1,2- and 1,3-dinitroglycerin, are found in plasma. Mean peak 1,2-and 1,3-dinitroglycerin plasma concentrations occur at approximately 15 minutes postdose. The elimination half-life of 1,2- and 1.3- dinitroglycerin is 36 and 32 minutes, respectively. The 1,2- and 1,3-dinitroglycerin metabolites have been reported to possess approximately 2% and 10% of the pharmacological activity of nitroglycerin. Higher plasma concentrations of the dinitro metabolites, along with their nearly 10-fold longer elimination half-lives, may contribute significantly to the duration of pharmacologic effect. Glycerol mononitrate metabolites of nitroglycerin are biologically inactive.

Elimination

Nitroglycerin plasma concentrations decrease rapidly with a mean elimination half-life of2 to 3 minutes. Half-life values range from 1.5 to 7.5 minutes. Clearance (13.6 L/min) greatly exceeds hepatic blood flow. Metabolism is the primary route of drug elimination.

Last reviewed on RxList: 8/24/2009

Nitrostat Medication Guide

 

PATIENT INFORMATION

If possible, patients should sit down when taking Nitrostat tablets. This eliminates the possibility of falling due to lightheadedness or dizziness.

Nitroglycerin may produce a burning or tingling sensation when administered sublingually; however, the ability to produce a burning or tingling sensation should not be considered a reliable method for determining the potency of the tablets. Headaches can sometimes accompany treatment with nitroglycerin. In patients who get these headaches, the headaches may be a marker of the activity of the drug.

Treatment with nitroglycerin may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol. Nitroglycerin should be kept in the original glass container, tightly capped.

Last reviewed on RxList: 8/24/2009

Nitrostat Consumer

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

NITROGLYCERIN EXTENDED-RELEASE CAPSULE – ORAL

(NYE-troe-GLIS-er-in)

USES: Nitroglycerin extended-release capsules are used to prevent chest pain (angina) in people with a certain heart condition (coronary artery disease). This medication belongs to a class of drugs known as nitrates. Angina occurs when the heart muscle is not getting enough blood. This drug works by relaxing and widening blood vessels so blood can flow more easily to the heart.

This medication will not relieve chest pain once it occurs. It is also not intended to be taken just before physical activities (such as exercise, sexual activity) to prevent chest pain. Other medications may be needed in these situations. Consult your doctor for more details.

HOW TO USE: Take this medication by mouth, usually 3 to 4 times daily or as directed by your doctor. It is important to take the drug at the same times each day. Do not change the dosing times unless directed by your doctor. The dosage is based on your medical condition and response to treatment.

Swallow this medication whole. Do not crush or chew the capsules. Doing so can release all of the drug at once and may increase your risk of side effects.

Use this medication regularly to get the most benefit from it. Do not suddenly stop taking this medication without consulting your doctor. Some conditions may become worse when the drug is suddenly stopped. Your dose may need to be gradually decreased.

Although unlikely, when this medication is used for a long time, it may not work as well and may require different dosing. Tell your doctor if this medication stops working well (for example, you have worsening chest pain or it occurs more often).

Nitrostat Consumer (continued)

SIDE EFFECTS: Headache, dizziness, lightheadedness, nausea, and flushing may occur as your body adjusts to this medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Headache is often a sign that this medication is working. Your doctor may recommend treating headaches with an over-the-counter pain reliever (such as acetaminophen, aspirin). If the headaches continue or become severe, tell your doctor promptly.

To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fainting, fast/irregular/pounding heartbeat.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US –

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada – Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using this medication, tell your doctor or pharmacist if you are allergic to it; or to similar drugs (such as isosorbide mononitrate); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: recent head injury, frequent stomach cramping/watery stools/severe diarrhea (GI hypermotility), lack of proper absorption of nutrients (malabsorption).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: anemia, low blood pressure, loss of too much body water (dehydration), other heart problems (such as recent heart attack).

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist that you are using this medication.

Older adults may be more sensitive to the side effects of this medication, especially dizziness and lightheadedness, which could increase the risk of falls.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk or if it may harm a nursing infant. Consult your doctor before breast-feeding.

Nitrostat Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious (possibly fatal) interactions may occur: drugs used to treat erectile dysfunction (such as sildenafil, tadalafil, vardenafil).

If you are currently using any of these medications, tell your doctor or pharmacist before starting nitroglycerin.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: rosiglitazone, certain drugs to treat migraine headaches (ergot alkaloids such as ergotamine), drugs that lower blood pressure (including alpha blockers such as tamsulosin).

This medication may interfere with certain laboratory tests (including blood cholesterol levels), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call their local poison control center. Symptoms of overdose may include: slow heartbeat, vision changes, severe nausea/vomiting, sweating, cold/clammy skin, bluish fingers/toes/lips.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as blood pressure monitoring) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Lifestyle changes such as dietary changes, exercise, and stopping smoking may help this drug work better. Talk to your doctor or pharmacist about lifestyle changes that might benefit you.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).